Abstract
SHP2 is the first oncogenic tyrosine phosphatase encoded by PTPN11, which plays a significant regulatory role in cancer and inflammation-related diseases. Although SHP2 allosteric inhibitors have been used in phase I/II clinical trials for solid tumors, whether SHP2 inhibition alleviates psoriasis remains unclear. Here we expressed and purified SHP2 related proteins, and established an enzyme activity screening system for different conformations of SHP2. We launched an iterative medicinal chemistry program and identified the lead compound, TK-453. Importantly, TK-453 possessed stronger affinity with SHP2 than SHP099, evidenced by the cocrystal structure of SHP2/TK-453, revealing that the additional aryl-S-aryl bridge in TK-453 induces a 1.8 Å shift of the dichlorophenyl ring and an approximate 20° deviation of the pyrazine ring plane relative to SHP099. Furthermore, TK-453 significantly ameliorated imiquimod-triggered skin inflammation in mice via inhibition of the IL-23/Th17 axis, proving that SHP2 is a potential therapeutic target for psoriasis.